Fumarate drugs rescue cardiac dysfunction in mouse models of Friedreich's ataxia

富马酸盐药物可挽救弗里德赖希共济失调小鼠模型的心功能障碍

• 批准号: 10320787
• 负责人: Elena N. Dedkova
• 金额: $ 39.25万
• 依托单位: UNIVERSITY OF CALIFORNIA AT DAVIS
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-12-20 至 2024-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10320787
• 关键词: Aconitate Hydratase; Address; Affect; Age; Animals; Ataxia; Biochemical; Biogenesis; Biological Assay; Body Weight decreased; Cardiac; Cardiac Output; Cardiomyopathies; Cell Death; Cessation of life; Clinical Data; Clinical Trials; Complex; Data; Defect; Development; Dose; Drug Kinetics; Drug usage; EFRAC; Enzymes; Equilibrium; FDA approved; Fibroblasts; Fibrosis; Freezing; Friedreich Ataxia; Fumarates; Gender; Hand Strength; Heart; Heart Abnormalities; Heart Hypertrophy; Heart failure; Histone Deacetylase; Histopathology; Human; Impairment; Inherited; Iron; Knockout Mice; Left; Left Ventricular Hypertrophy; Libraries; Longevity; Mediating; Mitochondria; Mitochondrial Proteins; Multiple Sclerosis; Mus; Muscle Mitochondria; Muscle function; Myocardial dysfunction; Myocardium; Myopathy; Necrosis; Neurologic Deficit; Oxidation-Reduction; Patients; Pharmaceutical Preparations; Pharmacotherapy; Physiological; Prodrugs; Proteomics; Psoriasis; Reaction Time; Recovery of Function; Role; Rotarod Performance Test; Safety; Sampling; Sensory; Signal Pathway; Skeletal Muscle; Stroke Volume; Succinate Dehydrogenase; Sulfur; Survival Analysis; Symptoms; Testing; Thick; Time; Tissues; Toxicology; Two-Dimensional Echocardiography; Ventricular; Weight; Wheelchairs; Work; base; cardioprotection; design; drug testing; efficacy testing; enzyme activity; frataxin; heart function; improved; in vivo; knock-down; mortality; mouse development; mouse model; multiple sclerosis treatment; mutant; novel therapeutic intervention; phase 1 study; pre-clinical; prevent; sex

Friedreich's Ataxia (FA) is the most common inherited recessive ataxia, for which there is no FDA-approved therapy. FA's pathophysiological mechanism is caused by the reduction of just one mitochondrial protein, frataxin (FXN), that functions in iron-sulfur (Fe-S) cluster biogenesis. Symptoms typically begin between the ages of 5 and 15 years and worsen over time. Although sensory and balance deficits put FA patients in wheelchairs, nearly all FA patients die of cardiomyopathy. Currently, there are no drug therapies that ameliorate FA cardiomyopathy and most with FA die of the cardiomyopathy in their 30s. We identified redox deficiency in FA human fibroblasts, and used this to screen a library of 1600 drugs already safely used in humans, to test for their ability to prevent cell death in FA. We identified dimethyl fumarate (DMF), a prodrug precursor of monomethyl fumarate (MMF), as the most protective among all tested drugs. DMF (also known as Tecfidera and Skilarence) is the FDA approved drug for treatment of multiple sclerosis (MS) and psoriasis. In the most physiological mouse model of FA (the FXNKD), we found that 1) DMF dose-dependently rescued FXN levels and the mitochondrial Fe-S cluster enzymes aconitase and succinate dehydrogenase activity in the heart; 2) DMF significantly rescued three critical cardiac deficits in mice that resemble human FA cardiac defects: a) left ventricular hypertrophy; b) decreased stroke volume; and c) decreased cardiac output. Preliminary data support the claim that DMF is providing mitochondrial->frataxin-> Fe-S cluster support via Nrf2-dependent mechanism. Additionally, we recently synthesized an alternative MMF prodrug called IMF, with improved pharmacokinetics that may be even more potent than DMF. Therefore, we hypothesize that fumarates DMF/IMF represent a novel therapeutic strategy that can potentially be repurposed for the lethal cardiomyopathy in FA. The aim of the current work is to determine the effects of DMF/IMF on the function of most affected tissues in FA (heart and skeletal muscles), and to determine the mechanism of protective action. DMF has already passed through FDA's safety, toxicology and DMPK hurdles, and thus could enter clinical trials much more quickly than a new compound that must pass through extensive safety and toxicology testing before it could be used in clinical trials. However, before attempting to use the drug in humans with FA, completion of the 'pre-clinical package' for DMF/IMF and their role for cardiac/skeletal muscle protection in FA are important, and can be addressed in the three Specific Aims. Aim 1 is designed to determine optimal dosing of DMF & IMF that rescue cardiac and skeletal muscles deficits. Aim 2 is designed to determine the mechanism responsible for functional recovery in the FXNKD mouse. Aim 3 is designed to determine whether optimal dosing of DMF/IMF extends the life span of mouse with cardiac-specific FXN KO (MCK-Cre). Cumulatively these aims will generate pre-clinical data for the potential use of DMF and IMF for lethal cardiomyopathy in FA. Because DMF is already approved for use in humans with safety/DMPK/toxicology and Phase I studies already completed, it has a greater opportunity to be 'fast-tracked' for treatment of cardiac myopathy in FA.

Friedreich共济失调(FA)是最常见的遗传性隐性共济失调，目前尚无FDA批准的治疗方法 心理治疗。FA的病理生理机制是由一种线粒体蛋白Frataxin(FXN)的减少引起的， 在铁-硫(铁-S)团簇生物发生中起作用。症状通常在5至15岁之间开始， 随着时间的推移会恶化。尽管感觉和平衡障碍使FA患者坐在轮椅上，但几乎所有FA患者都死于 心肌病。目前，还没有改善FA心肌病的药物疗法，大多数FA患者死于 30多岁的心肌病患者。 我们鉴定了FA人成纤维细胞的氧化还原缺陷，并利用这一点筛选了1600种药物的文库 在人类身上安全使用，以测试它们防止FA细胞死亡的能力。我们鉴定了富马酸二甲酯(DMF)， 富马酸单甲酯(MMF)的前药前体，是所有受试药物中保护性最强的。DMF(也称为 Tecfidera和Skiarence)是FDA批准的治疗多发性硬化症(MS)和牛皮癣的药物。在大多数情况下 生理性FA小鼠模型(FXNKD)，我们发现：1)DMF剂量依赖地挽救FXN水平和 心肌线粒体Fe-S簇酶、乌头酸酶和琥珀酸脱氢酶活性；2)DMF显著 挽救了类似人类FA心脏缺陷的三种严重的小鼠心脏缺陷：a)左心室肥厚；b) 每搏量减少；以及c)心输出量减少。初步数据支持DMF正在提供的说法 线粒体-Frataxin-&GT；Fe-S簇通过NRF2依赖机制支持。 此外，我们最近合成了一种名为IMF的替代MMF前体药物，具有更好的药代动力学 这可能比DMF更有效力。因此，我们假设富马酸DMF/IMF代表了一种新的 对于FA中的致命性心肌病，有可能改变治疗策略。当前工作的目的 目的是确定DMF/IMF对FA(心脏和骨骼肌)中受影响最大的组织功能的影响，并 确定保护作用的机制。DMF已通过FDA的安全性、毒理学和DMPK 障碍，因此可以更快地进入临床试验，而不是必须通过广泛的新化合物 在它可以用于临床试验之前，进行安全性和毒理学测试。然而，在试图将该药物用于 人类FA，DMF/IMF临床前方案的完成及其在心肌/骨骼肌中的作用 在FA中保护很重要，可以在三个具体目标中加以解决。目标1旨在确定最优 剂量DMF和IMF，以挽救心肌和骨骼肌缺陷。AIM 2被设计用来确定 负责FXNKD小鼠的功能恢复。AIM 3旨在确定最佳剂量的 DMF/IMF通过心脏特异性FXN KO(MCK-CRE)延长小鼠的寿命。累积起来，这些目标将 为DMF和IMF在FA中用于致死性心肌病的潜在用途生成临床前数据。因为DMF是 已经被批准用于人类，安全性/DMPK/毒理学和第一阶段研究已经完成，它有更大的 在FA中，心脏肌病的治疗将有机会被快速追踪。